Pruritus (itching) occurs in a variety of dermatoses with inflammation. It is known that pruritus is also sensed in internal diseases, pregnancy and vermination, and the pruritus is sometimes induced by drugs and by psychogenic reasons. Since quantitative and objective evaluation of pruritus is difficult, the study thereof has not been advanced, and the mechanism that induces pruritus has not yet been completely clarified. Reported substances which induce pruritus include histamine, substance P, bradykinin, proteinases, prostaglandins and opioid peptides.
For the treatment of pruritus, antihistamines and antiallergic drugs, which are oral drugs, have been mainly employed. External preparations such as antihistamines, adrenocortical steroid dermatologic preparations, nonsteroidal anti-inflammatory drugs, camphor, menthol, phenol, salicylic acid, tar, crotamiton, capsaicin, and humectants (urea, Hirudoid, and vaseline) have also been used. However, oral drugs have some problems, e.g. a long lag time before presenting effects, and adverse events such as suppressive effects on the central nervous system (drowsiness and malaise) and impairment of the gastrointestinal system. External preparations also have problems in that the antipruritic effect is insufficient, and especially, administration of steroid drugs for an extended period of time brings about systemic side effects such as decreased adrenal function as well as topical side effects such as rebound phenomenon, skin atrophy, steroid purpura, striae cutis distensae and steroid acne.
As for the findings concerning the relationship between the compounds having morphinan skeleton and pruritus, it has been reported that pruritus was induced when morphine was epidurally or intrathecally administered, opposite to the cases where the compounds used in the present invention are administered (J. H. Jaffe and W. R. Martin. Goodman and Gilman's Pharmacological Basis of Therapeutics, Macmillan, N.Y., 1985). On the other hand, it has been also reported the pruritus induced by intrathecally-administered morphine was suppressed by naloxone, an opioid antagonist (J. Bernstein et al. J. Invest. Dermatol., 78, 82-83, 1982), and severe pruritus in cases of cholestasia with hepathopathy was suppressed by nalmefene, an opioid antagonist (J. R. Thornton and M. S. Losowsky. Dr. Med. J., 297, 1501-1504, 1988). Further, morphinan compounds of which 6-position is substituted by a chain group, represented by the following general formula, which have antipruritic actions are also known (PCT International Publication WO 98/23290):

On the other hand, morphinan compounds having a nitrogen-containing cyclic group are known, which are described in J. Bernstein et al. J. Invest. Dermatol., 78, 82-83, 1982 and J. R. Thornton and M. S. Losowsky, Br. Med. J., 297, 1501-1504, 1988. The disclosed uses of the compounds are analgesic and antitussive only (J. Bernstein et al., J. Invest. Dermatol., 78, 82-83, 1982 and J. R. Thornton and M. S. Losowsky, Br. Med. J., 297, 1501-1504, 1988). In G. Simon et al. Tetrahedron. 50, 9757-9768, 1994, C. Simon et al., Synth. Commun. 22, 913-921, 1992 and L. M. Sayre et al., J. Med. Chem., 27, 1325-1335, 1984, only the compounds are described and no use thereof is disclosed (G. Simon et al., Tetrahedron, 50, 9757-9768, 1994, C. Simon et al. Synth. Commun. 22, 913-921, 1992 and L. M. Sayre et al., J. Med. Chem. 27, 1325-1335, 1984) (Use for the treatment of urinary frequency or urinary incontinence was disclosed after the priority date of this application (PCT international Publication WO 04/33457)). However, there is no constant relationship between the structures of these compounds as well as the pharmacological activities through opioid receptors and the like and the antipruritic action according to the present invention, so that the references do not infer the prominent and useful antipruritic action of the antipruritic according to the present invention characterized in that the morphinan structure has a nitrogen-containing cyclic group at its 6-position.
It could therefore be helpful to provide novel antipruritic useful for the therapy of pruritus accompanying various diseases.